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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:147.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation

Hong Du; Susan Schiavi; Nick Wan; Mark Levine; David P. Witte; Gregory A. Grabowski

From the Division and Program in Human Genetics (H.D., G.A.G.) and Division of Pathology and Laboratory Medicine (D.P.W.), Children’s Hospital Research Foundation, Cincinnati, OH, 45229; and Genzyme Corporation (S.S., N.W., M.L.), Cambridge, MA.

Correspondence to Gregory A. Grabowski, MD, Professor and Director, Division and Program in Human Genetics, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail greg.grabowski{at}cchmc.org

Objective— Proof of principle is presented for targeted enzyme supplementation by using lysosomal acid lipase to decrease aortic and coronary wall lipid accumulation in a mouse model of atherosclerosis.

Methods and Results— Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. -Mannosyl-terminated human lysosomal acid lipase (phLAL) was produced in Pichia pastoris, purified, and administered intravenously to such mice with either early or late lesions. phLAL injections reduced plasma, hepatic, and splenic cholesteryl esters and triglycerides in affected mice. phLAL was detected in hepatic Kupffer cells and in atheromatous foam cells. Repeated enzyme injections were well tolerated, with no obvious adverse effects. In addition, the coronary and aortic atheromatous lesions were (1) eliminated in their early stages and (2) quantitatively and qualitatively reduced in their advanced stages.

Conclusion— These results support the potential utility of lysosomal acid lipase supplementation for the treatment of atherosclerosis, a leading cause of mortality and morbidity in Westernized nations.

Key Words: lysosomal acid lipase • atherosclerosis • lesion • mice

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